Multi-tailed lipids and uses thereof

a technology of lipids and lipids, applied in biochemistry apparatus and processes, organic chemistry, fermentation, etc., can solve the problems of slow slowed development of genetic drugs, and difficult sirna delivery efficiency,

Active Publication Date: 2016-06-09
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018]Another aspect of the invention relates to methods of screening a library of compounds of Formula (I) to identify one or more compounds that are useful in the methods of the invention. The identified compound may be useful for deliver...

Problems solved by technology

However, the efficient delivery of siRNA is still a challenge in the development of siRNA therapeutics.
It is understood that the development of genetic drugs is slowed by the inability to deliver nucleic acids effectively in vivo.
However, despite promising data from ongoing clinical trials for the treatment of respiratory syncytial virus infection and liver cancers (see, e.g., Zamora et al., Am. J. Respir. Crit.
Despite the delivery successes met by some of ...

Method used

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  • Multi-tailed lipids and uses thereof
  • Multi-tailed lipids and uses thereof
  • Multi-tailed lipids and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of the Compounds

[0345]Recent high-throughput screens of lipid-like compounds indicate that structures with multiple short alkyl tails stemming from a polyamine core are able to facilitate efficient gene silencing (3, 16, 17). To synthesize pure multi-tailed compounds with varying polyamine head group architectures, a rapid and efficient two-step solvent free synthetic route was developed that requires neither protection / deprotection steps nor the use of costly and time-consuming chromatographic purification (see, e.g., Schemes 1 and 2). The first step involves a quantitative Michael addition between a primary amine 2 or secondary diamine 5 and propargyl acrylate 1. The resulting bis-alkyne modified amines 3 and 6 are subjected to a thiol-yne “click” photoaddition with decanethiol 4 in the presence of a catalyst (e.g., a photocatalyst, such as a photoinitiator). The thiol-yne reaction is rapid and efficient and yields pure four-tailed lipid products in only about 180 seco...

example 2

Biological Assays

General Methods

[0349]What is described herein is a systematic evaluation of multiple parameters associated with both the physicochemical properties and biological barriers to delivery for a group of lipid nanoparticles (LNPs). The approach involves mapping out the entire delivery pathway and evaluating the correlation between each property or delivery barrier and gene silencing (FIG. 1, steps 1-6). This systematic approach presents two potential advantages. First, the correlation of multiple physicochemical properties and biological barriers for a large set of LNPs with gene silencing allows for identification of relevant relationships between structure, biological function, and biological activity. Understanding these relationships will help improve the design of future therapeutic delivery vehicles. Second, a multi-parametric evaluation with LNPs may lead to the identification of parameters that can complement in vitro gene knockdown as a pre-screening tool for th...

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Abstract

The present invention provides multi-tailed lipid compounds, and salts and stereoisomers thereof, and methods of preparing the compounds. Also provided are compositions including a compound of the invention and an agent (e.g., an siRNA, mRNA, plasmid DNA, small molecule, protein, peptide). The present invention also provides methods, and kits using the compositions for delivering an agent to a subject (e.g., to the liver, spleen, or lung of the subject) or cell and for treating and/or preventing a range of diseases, such as genetic diseases, proliferative diseases, hematological diseases, neurological diseases, immunological diseases, gastrointestinal diseases (e.g., liver diseases), respiratory diseases (e.g., lung diseases), painful conditions, psychiatric disorders, metabolic disorders, and spleen diseases.

Description

RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional patent application, U.S. Ser. No. 61 / 839,616 filed Jun. 26, 2013, the entire contents of which is incorporated herein by reference.GOVERNMENT SUPPORT[0002]This invention was made with U.S. Government support under Grant No. R37-EB000244 awarded by the National Institutes of Health. The U.S. government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]The ability to silence genes via RNA interference (RNAi) was reported by Mello and Fire in 1998. See Fire et al., Nature (1998) 391:806-811. Since then, scientists have rushed to take advantage of the enormous therapeutic potential driven by targeted gene knockdown. This is evidenced by the fact that the first report of small interfering RNA (siRNA) mediated RNAi in human beings was reported only twelve years after the phenomenon was described in Caenorhabditis elegans. See Davis et al., Nature (2010) 464:106...

Claims

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Application Information

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IPC IPC(8): A61K47/22C07D207/09C12N15/113C07D295/15
CPCA61K47/22C07D295/15C07D207/09C12N2310/14C12N15/1137C12N2320/32C12N15/113C07C323/12A61K9/127
Inventor ALABI, AKINLEYE C.LOVE, KEVIN THOMASANDERSON, DANIEL GRIFFITHLANGER, ROBERT S.
Owner MASSACHUSETTS INST OF TECH
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